Overexpression Of apoE Research Articles

Expression of metabolic genes associated with changes in brain structure across the lifespan affects patients (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).

3144 Background: Longitudinal brain structure changes across the lifespan are associated with neurodegenerative disorders. We previously showed that genetic variants in dopamine and Parkinson’s disease genes are predictive and prognostic in mCRC. Indeed, the brain-gut axis is emerging as a critical player in CRC biology. Hence, we investigated whether the tumor gene expression of 3 metabolic genes involved in brain development and aging could affect treatment response in patients enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were included in the analysis. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of expression of 3 genes: APOE, DACH1, and GPR139. Likelihood ratio tests, hazard ratios and 95% confidence intervals were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ethnicity, ECOG PS, tumor location, number of metastatic sites, KRAS, MSI status, and treatment. Logrank P-values describe differences without adjustment for patient characteristics. Results: Both APOE and DACH1 (but not GPR139) met the 0.05 false discovery rate threshold for association with both PFS ( P = .00085, P = .015) and OS ( P = .021, P = .021, respectively) in the full Cox models. In cet-treated pts, APOE-high (H) showed significantly shorter PFS (median 9.2 vs 11.8 vs 13.0 months (mo), high vs low (as reference) logrank P = .0021) and OS (median 21.9 vs 35.8 vs 34.6 mo; logrank P = .0017) compared to APOE-median and -low, respectively. Opposite results were observed for DACH1, where DACH1-H tumors had longer PFS (median 14.5 vs 10.6 vs 8.07 mo; logrank P = .0011) and OS (median 39.4 vs 30.9 vs 21.5 mo; logrank P = .0021) when treated with cet. In bev-treated pts, similar results were observed with APOE-H showing shorter OS (median 25.8 vs 26.3 vs 37.5 mo; logrank P = .0016) and DACH1-H longer OS (median 36.5 vs 28.3 vs 22.4 mo; logrank P = .0017). No significant gene-treatment interaction was observed for either gene for PFS and OS. Conclusions: The tumor expression of metabolic genes associated with changes in the brain structure was prognostic in mCRC pts treated with first-line therapy. Notably, APOE and DACH1 have been recently reported to play a role in CRC where APOE overexpression has been associated with aggressive biological behavior whereas DACH1 has been shown to suppress CRC cell growth and invasion. Our results support this evidence and suggest that further investigation into the role of APOE and DACH1 in CRC biology and into their potential as targets for drug development is warranted. Trial Identifier: NCT00265850.

Immune landscape and the key role of APOE+ monocytes of lupus nephritis under the single-cell and spatial transcriptional vista.

Lupus nephritis (LN) is among the most common complication of systemic lupus erythematosus (SLE) with high mortality and morbidity. The analysis of LN kidney's local immune response through single-cell and spatial transcriptome enables the study of potential therapeutic targets. By single cell sequencing and spatial transcriptome, we profile cells from LN kidney and normal kidney tissues to characterize cellular composition and elucidate the potential upstream monocyte/macrophage (Mono/MΦ) initiating the auto-immune response. After the high-throughput synergy screening, we performed the immunofluorescence to identify the specific cells in LN patients. The function experiments were finished by flow cytometry and Elisa. By immunofluorescence and spatial transcriptome, we identified differential subsets of Mono/MΦ and demonstrated that they exhibit temporal expression of TIMP1, IL1B, SPP1 and APOE. With the function experiments, we found that the APOE+ Mono may be compensatorily increased in LN, and the capacity of antigen presenting was decreased with the overexpression of APOE. Furthermore, how do the LN-specific Mono/MΦ transport in and out the glomerulus to active the local immune response remains unclear. Our results showed that lymphangiogenesis occurred in LN kidneys but not in normal kidneys, suggesting the presence of a new lymphatic vessel may serve as a 'green channel' for LN-specific Mono/MΦ. In LN, APOE+ Mono are compensatorily elevated, with decreased antigen presenting ability and reduced secretion of interferons. The lymphangiogenesis in LN prompts the trafficking of Mono/MΦ in LN kidney.

2021 marks a new era for Alzheimer's therapeutics

2021 marks a new era for Alzheimer's therapeutics

Hub Gene and Its Key Effects on Diffuse Large B-Cell Lymphoma by Weighted Gene Coexpression Network Analysis.

Diffuse large B-cell lymphoma (DLBC) is a kind of tumor with rapid progress and poor prognosis. Therefore, it is necessary to explore new biomarkers or therapeutic targets to assist in diagnosis or treatment. This study is aimed at screening hub genes by weighted gene coexpression network analysis (WGCNA) and exploring the significance of overall survival (OS) in DLBC patients. Statistical data using WGCNA to analyze mRNA expression in DLBC patients came from The Cancer Genome Atlas (TCGA) dataset. After analyzing with clinical information, the biological functions of hub genes were detected. Survival analysis, Cox regression detection, and correlation analysis of the hub genes were carried out. The potential function of the hub gene related to prognosis was predicted by gene set enrichment analysis (GSEA). The results showed that APOE, CTSD, LGALS2, and TMEM176B expression in normal tissues was significantly higher than that in cancer tissues (P < 0.01). Survival analysis showed that patients with high APOE and CTSD were associated with better OS (P < 0.01). APOE and CTSD genes were mainly enriched in the regulation of ROS and oxidative stress. The two hub genes related to the prognosis of DLBC were identified and verified based on WGCNA. Survival analysis showed that the overexpression of APOE and CTSD in DLBC might be beneficial to the prognosis. These findings identified vital pathways and genes that may become new therapeutic targets and contribute to prognostic indicators.

Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease.

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

&lt;p&gt;Identification of Apolipoprotein E as a Potential Diagnostic Biomarker of Nasopharyngeal Carcinoma&lt;/p&gt;

PurposeApo-E, a secreted protein, is closely related to the migration and invasion of tumor cells. In this study, we aimed to analyze the expression of Apo-E in nasopharyngeal carcinoma (NPC) patients and cell lines, as well as its effects on NPC cell behavior.Patients and MethodsOur study included 35 patients with NPC from Zhongnan Hospital. Expression levels of Apo-E in patients with NPC were examined by quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemical (IHC) staining. Receiver operating characteristic (ROC) curves were analyzed using the SPSS 22 software to estimate the sensitivity and specificity of the Apo-E protein in diagnosing NPC. Additionally, the level of Apo-E in NPC cell lines (NP69, 6–10B, and 5–8F) was investigated by Western blotting and IHC.ResultsLevels of Apo-E were higher in NPC patients than in controls. Moreover, ROC analysis revealed that increased Apo-E in the serum of NPC patients may act as a potential biomarker for NPC diagnosis (Area under the curve 0.917). Furthermore, similar results were also identified in NPC cancer cell lines. RNA interference technology was used to overexpress the endogenous Apo-E in the NPC cell line 6–10B. Wound healing and transwell assays indicated that the overexpression of Apo-E increased the number of cell colonies and migration ability, respectively.ConclusionIn this study, we found that Apo-E was elevated in NPC patients and may act as a potential biomarker for NPC diagnosis. In addition, Apo-E was upregulated in NPC cell lines and promoted cell growth, migration, and invasion.

Lipoprotein profile and lipid metabolism of PXB-cells®, human primary hepatocytes from liver-humanized mice: proposal of novel in vitro system for screening anti-lipidemic drugs.

We investigated lipid metabolism in PXB-cells, which are human primary hepatocytes isolated from liver-humanized mice, and HepG2 and HuH-7 human hepatoma cell lines. Lipoprotein levels were higher in PXB-cells than in the 2 other cell lines, and PXB-cells mainly released triglycerides and cholesterol as very low density lipoprotein (VLDL), similar to actual liver tissue, whereas the major lipoprotein released from the 2 hepatoma cell lines was LDL. RT-PCR analysis demonstrated that the gene expression levels of apolipoprotein B100 (ApoB100), the apolipoprotein of VLDL/LDL, were similar in PXB-cells and HepG2 cells, while the overexpression of ApoC2, ApoC3, and ApoE, which are components of VLDL, but not LDL, was observed in PXBcells. A protein immunoassay revealed that ApoB100 levels secreted from PXB-cells and HuH-7 cells were similar; however, ApoC3 levels were higher in PXB-cells than in the two other cell lines. We also examined the anti-lipidemic activities of fenofibrate using this assay system. Fenofibrate suppressed lipoprotein production from PXB-cells in a dose-dependent manner mainly by activating the β-oxidation pathway. These results suggest that PXB-cells produce high levels of lipoproteins and are suitable for screening anti-lipidemic agents.

Apolipoprotein E Overexpression Is Associated With Tumor Progression and Poor Survival in Colorectal Cancer.

Apolipoprotein E (ApoE) plays a key role in tumorigenesis and progression, such as cell proliferation, angiogenesis and metastasis. ApoE overexpression was associated with aggressive biological behaviors and poor prognosis in a variety of tumor according to previous studies. This study aimed to assess the prognostic value and explore the potential relationship with tumor progression in colorectal cancer (CRC). We collected the expression profiling microarray data from the Gene Expression Omnibus (GEO), investigated the ApoE expression pattern between the primary CRC and liver metastasis of CRC, and then explored the gene with prognostic significance based on the TCGA database. ApoE high expression was associated with poor overall survival (OS, p = 0.015) and progression-free survival (PFS, p = 0.004) based on the public databases. Next, ApoE expression was evaluated in two CRC cohorts by immunohistochemistry, of whom 306 cases were stage II and 201 cases were metastatic liver CRC. In the cohort of the liver metastasis, the ApoE expression was increasing in normal mucosa tissue, primary colorectal cancer (PC), and colorectal liver metastases (CLM) in order. Meanwhile, the level of ApoE expression in stage II tumor sample which had no progression evidence in 5 years was lower than that in PC of synchronous liver metastases. The high ApoE expression in PC was an independent risk factor in both stage II (HR = 2.023, [95% CI 1.297–3.154], p = 0.002; HR = 1.883, [95% CI 1.295-2.737], p = 0.001; OS and PFS respectively) and simultaneous liver metastasis (HR = 1.559, [95% CI 1.096–2.216], p = 0.013; HR = 1.541, [95% CI 1.129–2.104], p = 0.006; OS and PFS respectively). However, the overexpression of ApoE could not predict the benefit from the chemotherapy in stage II. The study revealed that the relevance of the ApoE overexpression in CRC progression, conferring a poor prognosis in CRC patients especially for stage II and simultaneous liver metastasis. These finding may improve the prognostic stratification of patients for clinical strategy selection and promote CRC clinic outcomes.

Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages.

Apolipoprotein E (ApoE) belongs to a class of cellular proteins involved in lipid metabolism. ApoE is a polymorphic protein produced primarily in macrophages and astrocytes. Different isoforms of ApoE have been associated with susceptibility to various diseases including Alzheimer’s and cardiovascular diseases. ApoE expression has also been found to affect susceptibility to several viral diseases, including Hepatitis C and E, but its effect on the life cycle of HIV-1 remains obscure. In this study, we initially found that HIV-1 infection selectively up-regulated ApoE in human monocyte-derived macrophages (MDMs). Interestingly, ApoE knockdown in MDMs enhanced the production and infectivity of HIV-1, and was associated with increased localization of viral envelope (Env) proteins to the cell surface. Consistent with this, ApoE over-expression in 293T cells suppressed Env expression and viral infectivity, which was also observed with HIV-2 Env, but not with VSV-G Env. Mechanistic studies revealed that the C-terminal region of ApoE was required for its inhibitory effect on HIV-1 Env expression. Moreover, we found that ApoE and Env co-localized in the cells, and ApoE associated with gp160, the precursor form of Env, and that the suppression of Env expression by ApoE was cancelled by the treatment with lysosomal inhibitors. Overall, our study revealed that ApoE is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages that exerts its anti-HIV-1 activity through association with gp160 Env via the C-terminal region, which results in subsequent degradation of gp160 Env in the lysosomes.

Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production.

In hepatocytes, PLIN2 is the major protein coating lipid droplets (LDs), an organelle the hepatitis C virus (HCV) hijacks for virion morphogenesis. We investigated the consequences of PLIN2 deficiency on LDs and on HCV infection. Knockdown of PLIN2 did not affect LD homeostasis, likely due to compensation by PLIN3, but severely impaired HCV particle production. PLIN2-knockdown cells had slightly larger LDs with altered protein composition, enhanced local lipase activity and higher β-oxidation capacity. Electron micrographs showed that, after PLIN2 knockdown, LDs and HCV-induced vesicular structures were tightly surrounded by ER-derived double-membrane sacs. Strikingly, the LD access for HCV core and NS5A proteins was restricted in PLIN2-deficient cells, which correlated with reduced formation of intracellular HCV particles that were less infectious and of higher density, indicating defects in maturation. PLIN2 depletion also reduced protein levels and secretion of ApoE due to lysosomal degradation, but did not affect the density of ApoE-containing lipoproteins. However, ApoE overexpression in PLIN2-deficient cells did not restore HCV spreading. Thus, PLIN2 expression is required for trafficking of core and NS5A proteins to LDs, and for formation of functional low-density HCV particles prior to ApoE incorporation.This article has an associated First Person interview with the first author of the paper.

Diallyl disulphide inhibits apolipoprotein(a) expression in HepG2 cells through the MEK1-ERK1/2-ELK-1 pathway

BackgroundLipoprotein(a) [LP(a)] is implicated as a common and independent risk factor for cardiovascular diseases. The therapeutic options currently available for reducing plasma LP(a) concentrations are limited. Diallyl disulphide (DADS), the main component of garlic, regulates lipid metabolism in hepatocytes and adipocytes through ERK1/2 signalling. This study aimed to assess the effect of DADS on apolipoprotein(a) [apo(a)] in HepG2 cells. We also determined the effects of DADS on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms.MethodsWe examined the role of DADS on apo(a) expression in HepG2 cells by treating cell with different concentrations of DADS (10, 20, 40 and 80 μg/mL) for 24 h or treating cells with 40 μg/mL DADS for 0, 6, 12, 24 and 48 h. Then we used quantitative real-time PCR to analysis apo(a) mRNA levels, used Western blot to analysis apo(a) protein levels and used enzyme-linked immunosorbent assay to test apo(a) secreted levels. To farther determined the role of DADS, we applied Transfection of small interfering RNA to knockdown ELK-1levels and applied PD98059, a specific inhibitor of ERK1/2, to block ERK1/2 signal.ResultsThe results show DADS inhibited apo(a) at both the mRNA and protein levels in HepG2 cells in a dose-dependent manner. DADS-mediated inhibition of apoa(a) expression in HepG2 cells was attenuated when the cells were cultured in medium containing PD98059 (ERK1/2 inhibitor) or were transfected with siRNAs against MEK1 or ELK-1. Overexpression of apo(a) yielded similar results.ConclusionsThis study reveals that DADS can downregulate apo(a) expression in a dose-dependent manner via the MEK-ERK12-ELK-1 pathway.

Attenuation of acute rat renal allograft rejection by apolipoprotein E-mimetic Peptide.

In addition to its well-described role in lipid metabolism, apolipoprotein E (ApoE) exerts immunomodulatory functions. A protective role of ApoE and ApoE-mimetic peptide (ApoE(133-149)) application was documented in several inflammatory disorders. In this study, we test the hypothesis that ApoE(133-149) promotes renal allograft survival. Dark Agouti, Brown Norway, and Fischer 344 kidneys were transplanted to Lewis rats to investigate fatal and reversible acute rejection. Apolipoprotein E expression was assessed in intravascular leukocytes of renal grafts, in graft tissue and in recipient blood plasma. Recipients of Brown Norway kidneys were treated with ApoE(133-149), and graft survival was monitored until day 100. Graft infiltration, cytokine, and chemokine production were analyzed. Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression was reduced or remained unchanged. Animals treated with ApoE(133-149) showed prolonged allograft survival, which was associated with a reduced infiltration of CD8 and α/β T-cell receptor-expressing cells, diminished Granzyme B mRNA expression, and decreased caspase-3 activation. Endogenous ApoE overexpression and exogenous application of ApoE(133-149) seem to protect renal allografts from fatal acute rejection. This effect was associated with a reduced influx of cytotoxic T cells.

Inhibition of apolipoprotein A-I expression by TNF-alpha in HepG2 cells: requirement for c-jun.

Tumor necrosis factor alpha (TNF α) signals in part through the mitogen activated protein (MAP) kinase c-jun-N-terminal kinase (JNK). Activation of JNK has been shown to promote insulin resistance and dyslipidemia, including reductions in plasma high-density lipoprotein (HDL) and apolipoprotein A-I (apo A-I). To examine how TNF α-mediated JNK activation inhibits hepatic apo A-I production, the effects of c-jun activation on apo A-I gene expression were examined in HepG2 cells. Apo A-I gene expression and promoter activity were measured by Northern and Western blotting and transient transfection. Transient transfection and siRNA were used to specifically over-express or knockout c-jun, c-jun-N-terminal kinase-1 and -2 (JNK1 and JNK2, respectively) and mitogen-activated protein kinase-4 (MKK4). TNF α-treatment of HepG2 cells induced rapid phosphorylation of c-jun on serine 63. In cells treated with phorbol-12-myristate-13-acetate (PMA), apo A-I gene promoter activity was inhibited and apo A-I mRNA content and apo A-I protein secretion decreased. Likewise, over-expression of JNK1 and JNK2 inhibited apo A-I promoter activity. Over-expression of constitutively active MKK4, an upstream protein kinase that directly activates JNK, also inhibited apo A-I promoter activity, while over-expression of a dominant-negative MKK4 de-repressed apo A-I promoter activity in TNF α-treated cells. Inhibition of c-jun synthesis using siRNA but not a control siRNA prevented TNF α-mediated inhibition of apo A-I. These results suggest that the MKK4/JNK/c-jun signaling pathway mediates TNF α-dependent inhibition of apo A-I synthesis.

Expression and clinical significance of apolipoprotein E in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a poor prognosis. Our previous proteomic analysis found apolipoprotein E (ApoE) protein to be up-regulated in the sera of patients with PDAC. In this study, we sought to confirm this finding and investigate the relationship between ApoE and PDAC. We measured ApoE expression in tissues from PDAC patients and normal controls (NC) by real-time PCR, western blot, and immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was applied to measure the levels of ApoE and carbohydrate antigen 19-9 (CA19-9) in the sera from patients with PDAC and NC. Real-time PCR and western blots showed that the ApoE mRNA and protein levels were up-regulated in PDAC tissues. The immunohistochemical results revealed that overexpression of ApoE was detected in 43 of 55 (78.2 %) PDAC cases and 3 of 20 (15 %) NC. High levels of ApoE were more likely in PDAC patients with advanced T status and TNM stages (p = 0.023 and p = 0.018, respectively). The ELISA results also confirmed that ApoE levels were elevated in the sera of PDAC patients. The sensitivity and specificity for distinguishing PDAC from NC were 76.2 and 71.4 %, respectively, for ApoE, 66.7 and 85.7 %, respectively, for CA19-9, and 81.0 and 85.7 %, respectively, for their combination. These results suggest that ApoE may be a potential PDAC-related biomarker and alone or in combination with other markers may provide additional information for the diagnosis and clinical management of PDAC.

Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB

Apolipoprotein E (ApoE) plays a major role in the transport and metabolism of lipid. Other functions of ApoE include modulation of innate and adaptive immune responses. The expression of ApoE in osteoblasts and its relevance with bone formation have also been reported. However, the effect of ApoE on osteoclasts has not yet been examined. Here, we investigated the role of ApoE in osteoclast differentiation using bone marrow-derived macrophages (BMMs) and RAW264.7 cells. We found a down-regulation of ApoE gene expression during osteoclastic differentiation of those cells. Overexpression of ApoE in BMMs and RAW264.7 cells significantly blocked the induction of c-Fos and nuclear factor of activated T cell c1 (NFATc1), transcription factors critical for expression of osteoclast marker genes, by receptor activator of nuclear factor κB ligand (RANKL), the osteoclast differentiation factor. ApoE inhibited osteoclast differentiation, as measured by decreased number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNCs). In addition, ApoE reduced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase, H+ transporting, lysosomal 38kDa, V0 subunit d2 (ATP6v0d2), genes involved in cell–cell fusion during osteoclastogenesis. Knock-down of ApoE using a specific siRNA promoted the RANKL-mediated induction of osteoclast differentiation. While ApoE did not affect the activation of ERK, JNK, and p38 MAPK signaling pathways by RANKL, the phosphorylation of p65 trans-activation domain on serine 536 and transcription activity of NF-κB were reduced by ApoE overexpression. These findings suggest that ApoE plays an inhibitory role in osteoclast differentiation via the suppression of RANKL-dependent activation of NF-κB and induction of c-Fos and NFATc1.

ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with (3)H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P < 0.05), fecal neutral sterol excretion (P < 0.05), and in vivo RCT (P < 0.01), specifically within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.

Age-related changes of apolipoprotein D expression in female rat central nervous system with chronic estradiol treatment

Aging is associated with a reduction in metabolic functions, increased incidence of neurodegenerative diseases, and memory or cognitive dysfunction. With aging, a decrease in plasma estrogen levels, related to loss of gonadal function, occurs in females. Estrogens have neuroprotective effects and estradiol treatment improves some aspects of neuronal homeostasis affected by aging. In other way, recent studies show that apo D can play a neuroprotective role in some neuropathologies and during aging. The possible relation between estradiol treatment and the expression of apo D, during aging in the CNS, was investigated in female rats. Our results confirm an expression of apo D zone-dependent, in relation with aging, and an overexpression of apo D related to ovariectomy and estradiol treatment. This overexpression strengthens the idea that apo D plays a neuroprotective role in the CNS.

Apolipoprotein E mRNA is transported to dendrites and may have a role in synaptic structural plasticity

Although the dendritic localization and translation of a subset of mRNAs plays a pivotal role in synaptic plasticity, the dendritic mRNAs and their functions have been only minimally characterized thus far. In this study, we isolated mRNAs from Staufen2-containing ribonucleoprotein complexes, which function as modules for the transport of mRNA to the dendrites, and then constructed a cDNA library. Apolipoprotein E gene (APOE) mRNA was isolated from the dendritic mRNA-specific cDNA library. The specific localization of APOE mRNA was evaluated via in situ hybridization. The specific regions involved in the dendritic transport of APOE mRNA were determined using a visualization system employing green fluorescent protein-tagged bacteriophage MS2 RNA-binding protein. As a result, the proximal N-terminal or C-terminal regions of the ApoE-coding sequences were determined to be sufficient for dendritic transport. The level of dendritic APOE mRNA was significantly increased by depolarization-induced neuronal activity, but was reduced in the cell body regions. We assessed the functions of neuronal ApoE. The reduction of ganglioside GM1 by cholesterol depletion was completely blocked by ApoE over-expression. In addition, ApoE over-expression increased the immunoreactivity of the post-synaptic density 95 kDa antibody in the dendrites. These findings indicate that neuronal ApoE may be relevant to lipid rafts or synaptic structural plasticity.

Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer

Many human lung cancer cell lines express apolipoprotein E (ApoE), especially cells derived from malignant pleural effusions (MPE) in patients with lung adenocarcinoma. This study aimed to investigate the influence of ApoE expression on lung cancer. In lung cancer tissues, ApoE expression was more frequently found in malignant pleural effusions (MPE)-associated lung adenocarcinoma than in lung adenocarcinoma or squamous cell carcinoma without MPE ( P < 0.05), indicating that ApoE is associated with the pathogenesis of MPE in patients with lung adenocarcinoma. Next, we examined the roles of ApoE in an MPE-derived lung adenocarcinoma cell line that endogenously over-expresses ApoE, PC14PE6/AS2 (AS2). In that experiment we inhibited ApoE expression by transfection of a plasmid carrying ApoE siRNAs into AS2 cells to generate AS-S2 and AS-S3 cells. Compared to vector-control cells and parental AS2 cells, AS2-S2 and AS2-S3 cells grew slower ( P < 0.05), were more sensitive to cisplatin, and had significantly impaired cellular migration ( P < 0.05). Furthermore, over-expression of ApoE was independently associated with poor survival in lung adenocarcinoma patients who had MPE at the time of diagnosis ( P < 0.001). Conclusively, ApoE over-expression promotes cancer proliferation and migration and contributes to an aggressive clinical course in patients with lung adenocarcinoma and MPE.

Apolipoprotein E limits oxidative stress-induced cell dysfunctions in human adipocytes

Oxidative stress in adipose tissue constitutes a pathological process involved in obesity-linked metabolic disorders. Apolipoprotein E (apoE), which exhibits antioxidant properties in plasma and brain, is highly produced by adipose tissue and adipocytes. In this study, we investigated the role of apoE in the human adipocyte response to oxidative stress. We first demonstrated that apoE secretion by adipocytes was stimulated by oxidative stress. We also observed that apoE overexpression protected adipocytes from hydrogen peroxide-induced damages, by mitigating intracellular oxidation and exerting extracellular antioxidant properties. Our findings clearly show a novel antioxidant role for apoE in adipose tissue.